PDBsum entry 4id7

Transferase/transferase inhibitor

PDB id: 4id7

Contents

Protein chain

268 a.a.

Ligands

1G0

SO4

Waters ×6

PDB id:

4id7

Name:

Transferase/transferase inhibitor

Title:

Ack1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4- phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol

Structure:

Activated cdc42 kinase 1. Chain: a. Fragment: kinase domain, unp residues 117-389. Synonym: ack-1, tyrosine kinase non-receptor protein 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ack1, tnk2

Resolution:

3.00Å R-factor: 0.213 R-free: 0.259

Authors:

M.Jin,J.Wang,A.Kleinberg,M.Kadalbajoo,K.Siu,A.Cooke,M.Bittner,Y.Yao, A.Thelemann,Q.Ji,S.Bhagwat,A.P.Crew,J.Pachter,D.Epstein, M.J.Mulvihill

Key ref:

M.Jin et al. (2013). Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors. Bioorg Med Chem Lett, 23, 979-984. PubMed id: 23317569

Date:

11-Dec-12 Release date: 30-Jan-13

Protein chain

Q07912  (ACK1_HUMAN) -  Activated CDC42 kinase 1 from Homo sapiens

Seq: 1038 a.a.

Struc: 268 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺
• Enzyme class 3: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Bioorg Med Chem Lett 23:979-984 (2013)

PubMed id: 23317569

Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors.

M.Jin, J.Wang, A.Kleinberg, M.Kadalbajoo, K.W.Siu, A.Cooke, M.A.Bittner, Y.Yao, A.Thelemann, Q.Ji, S.Bhagwat, K.M.Mulvihill, J.A.Rechka, J.A.Pachter, A.P.Crew, D.Epstein, M.J.Mulvihill.

ABSTRACT

This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors.